Serotonergic enhancement of circadian responses to light: role of the raphe and intergeniculate leaflet

Abstract

Light serves as the primary stimulus that synchronizes the circadian clock in the suprachiasmatic nucleus (SCN) to the external day/night cycle. Appropriately timed light exposure can reset the phase of the circadian clock. Some serotonergic drugs that bind to the serotonin 1A receptor can enhance phase shifts to light. The mechanism by which this potentiation occurs is not well understood. In this study, we examined where one of these drugs, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride (BMY7378), might be working in the hamster brain. Systemic (5 mg/kg), intra-dorsal raphe and intra-median raphe (both 15.6 nmol in 0.5 μL), but not intra-SCN (7.8 nmol or 15.6 nmol in 0.5 μL) injections of BMY7378 significantly potentiated phase shifts to light. Potentiation of photic shifts persisted when serotonergic innervation of the SCN was lesioned with infusions of the serotonin neurotoxin 5,7-dihydroxytryptamine into the SCN. Light-induced c-Fos expression in the rostral and caudal intergeniculate leaflet (IGL) was attenuated with systemic BMY7378, suggesting that the IGL may be involved in this response. Both complete IGL lesions and depletion of serotonergic innervation of the IGL prevented systemic BMY7378 from potentiating photic phase shifts. Together, these findings suggest that the mechanism by which BMY7378 enhances photic responses is by changing the activity of the raphe nuclei to influence how the IGL responds to light, which subsequently influences the SCN as one of its downstream targets. Identification of the network that underlies this potentiation could lead to the development of useful therapeutic interventions for treating sleep and circadian disorders.

Chronic BMY7378 treatment alters behavioral circadian rhythms

“…The present study examined the effects of chronic BMY7378 treatment on circadian behavior in male hamsters. BMY7378 is a 5‐HT 1A mixed agonist/antagonist that potentiates phase advances to light when acutely administered systemically (Byku & Gannon, ; Gannon, ; Smith et al ., , ). We found that chronic BMY7378 administration significantly advanced the phase angle of entrainment and decreased the amplitude of activity in the early part of the night.…”

“…The 5‐HT 1A receptor mixed agonist/antagonist 8‐[2‐[4‐ (2‐Methoxyphenyl)‐1‐piperazinyl] ethyl]‐8‐azaspiro [4.5] decane‐7, 9‐dione dihydrochloride (BMY7378, Sigma Aldrich, Oakville, ON, USA) was dissolved in physiological saline and administered through osmotic mini pumps. Previously, we had examined the acute effects of this drug (Smith et al ., ,c) at a dose of 5 mg/kg. Here, we elected to use this same dose but spread over the full 24 h day (i.e., 5 mg/kg/day).…”

“…5‐HT levels in the SCN are highest during periods of high locomotor activity, most notably during the early night for nocturnal rodents (Dudley et al ., ). In both mice and hamsters, responses to light are generally inhibited by 5‐HT agonists (Glass et al ., ; Rea et al ., ; Pickard et al ., , ; Pickard & Rea, ; Weber et al ., ; Rea & Pickard, ; Antle et al ., ; Smith et al ., ; Basu et al ., ) and are enhanced by 5‐HT antagonists (Moriya et al ., ; Byku & Gannon, ; Gannon, , ; Smart & Biello, ; Takahashi et al ., ; Gannon & Millan, ; Lall & Harrington, ; Kessler et al ., ; Sterniczuk et al ., ; Lungwitz & Gannon, ; Smith et al ., ). Of the various 5‐HT receptor subtypes, the 5‐HT 1A , 5‐HT 1B and 5‐HT 7 receptors seem to be important in modulating photic responses (Rea & Pickard, ; Smith et al ., , ).…”

“…The serotonergic system plays a role in modulating the magnitude of circadian responses to light (Mistlberger & Antle, ; Rea & Pickard, ). Both serotonin (5‐HT) and serotonergic drugs can modulate responses to light (Weber et al ., ; Morin, ; Rea & Pickard, ; Smith et al ., , , ).…”

“…A third class of compounds, termed mixed agonist‐antagonists, acts as agonists at presynaptic somatodendritic 5‐HT 1A autoreceptors in the raphe nuclei and as antagonists at post‐synaptic 5‐HT 1A receptors in the SCN (Rydelek‐Fitzgerald et al ., ; Claustre et al ., ; Gannon, ). Four specific compounds have been identified that exhibit this pharmacological profile: NAN‐190 (Rea et al ., ; Lall & Harrington, ; Kessler et al ., ; Sterniczuk et al ., ; Smith et al ., ), BMY7378 (Byku & Gannon, ; Gannon, ; Lungwitz & Gannon, ; Smith et al ., ), S15535 (Gannon, ) and MKC‐242 (Moriya et al ., ; Takahashi et al ., ). They are of particular interest as they enhance light‐induced resetting of the circadian clock in mice and hamsters by up to 400%.…”